Modulators of amyloid-beta production

Abstract

As described herein, the present invention provides compounds useful for treating or lessening the severity of a neurodegenerative disorder. The present invention also provides methods of treating or lessening the severity of such disorders wherein said method comprises administering to a patient a compound of the present invention, or composition thereof. Said method is useful for treating or lessening the severity of, for example, Alzheimer's disease.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         each of Ring A, Ring B, Ring C, and Ring D is independently saturated, partially unsaturated or aromatic; 
         R 1  and R 2  are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N(R) 2 , or a suitably protected amino group, or R 1  and R 2  are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each R is independently hydrogen, an optionally substituted C 1-6  aliphatic group, or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein:
 two R on the same nitrogen atom are optionally taken together with said nitrogen atom to form a 3-8 membered saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         R 3  and R 5  are each independently selected from halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 , wherein R 3  and R d  optionally form an epoxide or R 5  and R d  optionally form an epoxide; 
         R 6  and R 7  are each independently selected from halogen, R, OR, SR, or N(R) 2 , or R 6  and R 7  are taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated, or awl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         T is independently a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C 1-10  bivalent hydrocarbon chain wherein up to two methylene units of T are optionally and independently replaced by —O—, —N(R x )—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —, wherein two adjacent methylene units of T are optionally taken together with their intervening atoms to form an epoxide; 
         R 4  is CN, C(R′) 3 , C(R′) 2 C(R″) 3 , R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ; 
         each of R′ and R″ is independently selected from R, OR, SR, SO 2 R, OSO 2 R, ═P(R) 3 , N(R) 2 , NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ; 
         each of a, b, c, and d is 0-2; 
         each of R a , R b , and R c  is independently halogen, CN, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , O(CO)N(R) 2 , ═O, ═S, or ═NH(R), wherein:
 two R a  groups, or an R a  group and R 1 , on adjacent carbon atoms are optionally taken together with their intervening atoms to form an epoxide; 
 two R b  groups, or an R b  group and R 5 , on adjacent carbon atoms are optionally taken together with their intervening atoms to form an epoxide; or 
 two R c  groups, or an R c  group and either R 2  or R 3 , on adjacent carbon atoms are optionally taken together with their intervening atoms to form an epoxide; 
 
         each R d  is independently halogen, CN, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , O(CO)N(R) 2 , ═O, ═S, or ═NH(R), wherein:
 two R d  groups on adjacent carbon atoms of Ring D are optionally taken together with their intervening atoms to form an epoxide; 
 two R d  groups on the same carbon atom of Ring D are taken together to form an optionally substituted, straight or branched C 1-10  alkylidene group; or 
 two R d  groups on the same carbon atom of Ring D are taken together to form an optionally substituted, saturated or unsaturated, 4-7 membered ring, having 0-2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein said ring formed thereby is spiro fused to Ring D; 
 
         Q is a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C 1-6  bivalent hydrocarbon chain wherein up to two methylene units of Q are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —; and 
         R 8  is R, a suitably protected hydroxyl group, a suitably protected thiol group, a suitably protected amino group, an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a detectable moiety, a polymer residue, a peptide, or a sugar-containing or sugar-like moiety. 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  and R 2  are each independently R or OR. 
     
     
         3 . The compound according to  claim 1  wherein R 1  and R 2  are taken together to form a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         4 . The compound according to  claim 3 , wherein R 1  and R 2  are taken together to form a 3-6 membered saturated carbocyclic ring. 
     
     
         5 . The compound according to  claim 4 , wherein said compound is of formula I-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The compound according to  claim 5 , wherein said compound is of formula I-b, I-c, or I-d: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The compound according to any of  claims 1  to  6 , wherein R d  is R, OR, CN, ═O, or a suitably protected hydroxyl group. 
     
     
         8 . The compound according to any of  claims 1 - 6 , wherein d is 2 and two R d  groups are taken together with their intervening atoms to form an epoxide to form a compound of formula I-e or I-f: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The compound according to any of  claims 1 - 6 , wherein d is 2 and two R d  groups on the same carbon atom are taken together to form an optionally substituted, straight or branched C 1-10  alkylidene group. 
     
     
         10 . The compound according to any of  claims 1  to  9 , wherein T is a straight or branched C 1-4  bivalent hydrocarbon chain wherein one or two methylene units of T is replaced by —C(O)—, —O—, —N(R)—, or —S—. 
     
     
         11 . The compound according to any of  claims 1  to  9 , wherein T is a straight or branched C 1-4  bivalent hydrocarbon chain, wherein two adjacent methylene units of T are taken together to form an epoxide. 
     
     
         12 . The compound according to any of  claims 1  to  10 , wherein T is —CH(CH 3 )CH 2 CH 2 C(═O)CH(CH 3 )—, —CH(CH 3 )CH 2 CH 2 CH═CH—, —CH(CH 3 )CH 2 CH 2 —, ═CH—, —CH(CH 3 )CH 2 C(═O)—, or —CH(CH 3 )CH═CH—. 
     
     
         13 . The compound according to any of  claims 1  to  12 , wherein R 4  is R, halogen, OR, C(O)OR, or CN. 
     
     
         14 . The compound according to any of  claims 1  to  13 , wherein b is 1 and said compound is of formula I-h: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The compound according to  claim 14 , wherein R′ is ═O, R, OR, or a suitably protected hydroxyl group. 
     
     
         16 . The compound according to any of  claims 1  to  15 , wherein Q is a an optionally substituted straight or branched, saturated or unsaturated, C 1-2  bivalent hydrocarbon chain wherein up to one methylene unit of Q is optionally replaced by —O—, —N(R)—, or —S—. 
     
     
         17 . The compound according to any of  claims 1  to  16 , wherein R 8  is a suitably protected hydroxyl group. 
     
     
         18 . The compound according to any of  claims 1  to  17 , wherein said compound is of formula III, III-a, IV, or IV-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         19 . The compound according to any of  claims 1  to  17 , wherein said compound is of formula V-a, V-b, V-c, V-d, VI-a, or VI-b: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         20 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . A composition comprising a compound according to any of  claims 1  to  20 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         22 . A method for inhibiting amyloid-beta peptide production in a patient, wherein said method comprises administering to said patient a composition according to  claim 21 . 
     
     
         23 . The method according to  claim 22 , wherein said method does not affect Notch processing. 
     
     
         24 . The method according to  claim 22 , wherein amyloid-beta (1-42) peptide levels are reduced and amyloid-beta (1-40) peptide levels are not substantially reduced. 
     
     
         25 . The method according to  claim 24 , wherein the level of at least one of amyloid-beta (1-37) and amyloid-beta (1-39) is increased. 
     
     
         26 . A method for treating or lessening the severity of a disorder associated with amyloid-beta (1-42) peptide, wherein said method comprises administering to a patient a composition according to  claim 21 . 
     
     
         27 . The method according to  claim 26 , wherein said disorder is Alzheimer's disease, Parkinson's disease, Down's syndrome, inclusion body myositis, cerebral amyloid angiopathy, mild cognitive impairment, Lewy body dementia, Parkinson's disease, cataract, a Tauopathy, Huntington's disease, ALS/Lou Gerhig's disease, Type 2 diabetes, Transthyretin amyloid disease, prion disease, or CJD. 
     
     
         28 . The method according to  claim 27 , wherein said disorder is Alzheimer's disease, Parkinson's disease, or Down's syndrome. 
     
     
         29 . A method for reducing amyloid-beta (1-42) peptide levels in a patient, wherein said method comprises administering to said patient a composition according to  claim 21 . 
     
     
         30 . A method for reducing amyloid-beta (1-42) peptide levels in a cell, comprising contacting said cell with a compound according to any of  claims 1  to  20 .